Three out of every 100 babies are born with a structural malformation in the US alone. These birth defects are a leading cause of infant mortality, nationally and globally. Children who survive with birth defects often experience a diminishing quality of life and impose a substantial social and economic burden. Although birth defects pose a significant public health problem, clinical and public heath efforts to prevent most birth defects do not exist. The lack of evidence regarding etiology of most nonsyndromic birth defects represents a major barrier in establishing prevention programs. In 1997, the National Birth Defects Prevention Study (NBDPS) was created to investigate these complex etiologies. With the phasing out of the NBDPS, the CDC has created a new initiative building on the NBDPS findings - Birth Defects Study to Evaluate Pregnancy exposureS (BD- STEPS). The Arkansas Center for Birth Defects Research and Prevention, a participant in the NBDPS for 16 years, is dedicated to understanding the causes of birth defects and welcomes the opportunity to continue to contribute to an evidence base that will facilitate development of effective prevention strategies. We are well positioned to build on the foundation of the Arkansas Center by identifying maternal exposures in early pregnancy that may be amenable to early prevention. The long-term goal of the Arkansas Center is to prevent or significantly reduce the occurrence of birth defects. We propose, therefore, to identify early pregnancy exposures that may be modified to decrease the occurrence of selected birth defects by participating in the BD-STEPS; discover gene-environment interactions that lead to birth defects by supporting high-throughput genomic and epigenomic analyses of biological samples collected from NBDPS and BD-STEPS participants using institutional and extramural funds that augment CDC funding; help develop future generations of birth- defect researchers by training and mentoring junior researchers in data analysis, manuscript preparation, and other study-related activities. Through our studies, we will maintain a leading role in establishing clinical and public health strategies to prevent birth defects.